The long term goals of the project are to design and develop synthetic methods to obtain modified derivatives of trans-retinoic acid (t-RA)but which contain a heteroatom and are flexible. This type of retinoid has been labelled "heteroarotinoid" and has reduced toxicity compared t-RA. Preliminary work has indicated that such molecules have the ability to destroy cancer cells, especially those which are present in the epithelial layers of the skin. Thus, the work has long term ramifications for the treatment of skin cancer. Such specificity in activity of the heteroarotinoid suggest that it is probably the retinoic acid receptor gamma (RARgamma) specific with respect to activation. With the capability to "turn on" RARgamma by a specific ligand, such as a heteroarotinoid, is significant for inducing normal cell differentiation. The design of such ligands will include the incorporation of a flexible linking group between two aryl rings which will allow the ligand to be accommodated by the receptor and initiate its function. Consequently, this type of receptor activation is highly likely to be critical for correcting abnormal cell development such as in cancer.